Methods and formulations for reducing bovine emissions

ABSTRACT

The present disclosure provides methods and formulations for reducing ammonia and carbon dioxide emissions from a bovine using lubabegron, or a physiologically acceptable salt thereof. The present disclosure also provides bovine feed additives and bovine feed compositions.

Ammonia is the most abundant alkaline gas in the atmosphere. Inaddition, it is a major component of total reactive nitrogen. Recentstudies have indicated that ammonia emissions have been increasing overthe last few decades on a global scale. This is a concern becauseammonia plays a significant role in the formation of atmosphericparticulate matter, visibility degradation and atmospheric deposition ofnitrogen to sensitive ecosystems. Additionally, carbon dioxide is agreenhouse gas linked to global warming. Thus, the increase in ammoniaand carbon dioxide emissions negatively influences environmental andpublic health. Bovines, and particularly cattle, are major emitters ofammonia and contribute significantly to carbon dioxide emissions.Ammonia is generated and emitted by bovines during their digestiveprocess, as well as emitted from bovine wastes as they break down.

Different approaches have been used to control ammonia and carbondioxide emissions from bovines. One set of methods for reducing ammoniaand carbon dioxide emissions are dietary manipulation strategies. Onesuch approach applied to reducing both ammonia and carbon dioxideemissions is to reduce the amount of protein fed to the bovine. However,such a lower protein approach can lead to lesser amounts or sloweraccumulation of desired bovine muscle. In addition to dietarymanipulation strategies, many other practices have been utilized forreducing ammonia emissions, such as filtration of emissions andparticles, building impermeable barriers to prevent the movement ofammonia emissions, and control strategies for feces and urine in bovineraising operations. Many of these practices are costly, inconvenient,and of limited benefit. Therefore, there exists a need for alternativesfor reducing bovine ammonia and carbon dioxide emissions. Preferably,such alternatives decrease the inconvenience, drawbacks, and/or cost ofone or more of the current approaches.

U.S. Pat. No. 6,730,792 ('792) discloses lubabegron and salts thereoffor use in treating Type II diabetes and obesity and for binding to andactivating the β₃ receptor. Additionally, '792 states that in non-human,non-companion animals, the compounds of formula I described therein areuseful for increasing weight gain and/or improving the feed utilizationefficiency and/or increasing lean body mass and/or decreasing birthmortality rate and increasing post/natal survival rate. However,lubebagron or salts thereof was not known to reduce ammonia and/orcarbon dioxide emissions from bovine.

The present invention provides a method of reducing ammonia and/orcarbon dioxide emissions from a bovine in need thereof comprising orallyadministering to the bovine lubabegron, or a physiologically acceptablesalt thereof.

Another aspect of the present disclosure provides lubabegron, or aphysiologically acceptable salt thereof, for use in reducing ammoniaand/or carbon dioxide emissions from a bovine.

Another aspect of the present disclosure provides lubabegron, or aphysiologically acceptable salt thereof, for use in reducing ammoniaand/or carbon dioxide emissions from a bovine wherein said lubabegron isto be orally administered.

Another aspect of the present disclosure provides a bovine feed additivewhich comprises lubabegron, or a physiologically acceptable saltthereof, and a suitable carrier therefor, wherein said additive is forthe reduction of ammonia and/or carbon dioxide emissions.

Another aspect of the present disclosure provides an animal feed forreducing ammonia and/or carbon dioxide emissions from a bovine whichcomprises a bovine feed and lubabegron, or a physiologically acceptablesalt thereof.

Lubabegron, or a physiologically acceptable salt thereof, such aslubabegron fumarate, may be made by processes known in the art. Thehemifumarate salt of lubabegron is known as lubabegron fumarate (CASRegistry Number 391926-19-5). For example, the processes described inU.S. Pat. No. 6,730,792 are illustrative processes that may be used tomake lubabegron, or a physiologically acceptable salt thereof.

As used herein, the term “bovine” refers to an animal that is a memberof the biological subfamily Bovinae, including but not limited tocows/cattle, bison, African buffalo, and water buffalo. In preferredembodiments, the animal is a cow. As used herein, the term “cow” is abovine of either sex or age, and is a member of the biological genusBos, including the species Bos taurus and Bos indicus. Cows in a groupare commonly known as cattle. As such, the term cow includes dairycattle, beef cattle, bulls, heifers, oxen, and steers.

As used herein, “reducing ammonia emissions” from a bovine treated withlubabegron, or a physiologically acceptable salt thereof, refers toreducing emitted ammonia gas relative to a bovine not treated withlubabegron, or a physiologically acceptable salt thereof. In someembodiments, the reduction is from about 10 to about 30% in ammoniaemissions when compared to an untreated animal. In some embodiments, thereduction is from about 15 to about 25% in ammonia emissions. In someembodiments, the reduction of ammonia emissions from a bovine does notsignificantly negatively affect the bovine, such as, for example,lowering body weight, or decreasing meat and eating quality. In someembodiments, the reduction is per pound of live weight of the bovine.Live weight means the weight of the bovine while alive. In someembodiments, the reduction is per pound of hot carcass weight of thebovine. Hot carcass weight is the weight of a bovine carcass prior tochilling with its hide, head, gastrointestinal tract, and internalorgans removed. In some embodiments, the reduction of ammonia isaccompanied by an increase in hot or live carcass weight. In someembodiments, the bovine is in confinement for slaughter whenadministered lubabegron, or a physiologically acceptable salt thereof.

As used herein, “reducing carbon dioxide emissions” from a bovinetreated with lubabegron, or a physiologically acceptable salt thereofrefers to reducing emitted carbon dioxide gas relative to a bovine nottreated with lubabegron, or a physiologically acceptable salt thereof.In some embodiments, the reduction is about 9% in carbon dioxideemissions when compared to an untreated animal when carbon dioxideemissions are standardized to animal live weight. In some embodiments,the reduction is about 10% in carbon dioxide emissions when compared toan untreated animal when carbon dioxide gas emissions are standardizedby animal hot carcass weight. In some embodiments, the reduction ofcarbon dioxide emissions from a bovine does not significantly negativelyaffect the bovine, such as, for example, lowering body weight, ordecreasing meat and eating quality. In some embodiments, the reductionis per pound of live weight of the bovine. Live weight means the weightof the bovine while alive. In some embodiments, the reduction is perpound of hot carcass weight of the bovine. Hot carcass weight is theweight of a bovine carcass prior to chilling with its hide, head,gastrointestinal tract, and internal organs removed. In someembodiments, the reduction of carbon dioxide is accompanied by anincrease in hot or live carcass weight. In some embodiments, the bovineis in confinement for slaughter when administered lubabegron, or aphysiologically acceptable salt thereof. Lubabegron, or aphysiologically acceptable salt thereof, can be formulated for oraladministration, and such formulations include animal feeds and feedadditives. In some embodiments, the administration is carried out byincluding lubabegron, or a physiologically acceptable salt thereof, inan animal (bovine) feed. The animal feed may be a dry feed or a liquidfeed, and includes a bovine's drinking water containing lubabegron, or aphysiologically acceptable salt thereof. Such animal feeds may includelubabegron, or a physiologically acceptable salt thereof, combined oradmixed with suitable feedstuffs commonly employed in the feeding ofbovines. Typical feedstuffs commonly employed include corn meal, corncobgrits, soybean meal, alfalfa meal, rice hulls, soybean mill run,cottonseed oil meal, bone meal, ground corn, corncob meal, wheatmiddlings, limestone, dicalcium phosphate, sodium chloride, urea,distillers dried grain, vitamin and/or mineral mixes, cane molasses orother liquid carriers and the like. Such feedstuffs promote a uniformdistribution and administration of lubabegron, or a physiologicallyacceptable salt thereof. In some embodiments, feedstuffs containinglubabegron, or a physiologically acceptable salt thereof, is provided toa bovine ad libitum (i.e., “at will”).

While a particular embodiment for orally administering lubabegron, or aphysiologically acceptable salt thereof, is via daily feed rations,lubabegron, or a physiologically acceptable salt thereof, can beincorporated into salt blocks and mineral licks, as well as being addeddirectly to lick tank formulations or drinking water for convenient oralconsumption. Lubabegron, or a physiologically acceptable salt thereof,can also be administered orally by bolus or gavage treatment.

In some embodiments, feed additives are provided which includelubabegron, or a physiologically acceptable salt thereof, and one ormore suitable carriers. The feed additive may be a dry feed additive ora liquid feed additive. The feed additives are formulated such that,when added with other materials, an animal feed is formed which willprovide a desired concentration of lubabegron, or a physiologicallyacceptable salt thereof, in the animal feed, and/or provide the desireddose of lubabegron, or a physiologically acceptable salt thereof, to thebovine upon the bovine's consumption of the animal feed. Premixes arerecognized terms in the art for certain feed additives. They may besolid or liquid. A mineral premix is a composition which is intended forformation of an animal feed and which comprises desired kinds andamounts of minerals, in particular trace minerals. A vitamin premix is acomposition which is intended for formation of an animal feed and whichcomprises desired kinds and amounts of vitamins. Some premixes includeboth vitamins and minerals. As such, feed additives includes premixessuch as mineral premixes, vitamin premixes, and premixes which includeboth vitamins and minerals.

In some embodiments, lubabegron, or a physiologically acceptable saltthereof, is administrated to the bovine up to at least 91 days prior toslaughter of the bovine. In some embodiments, lubabegron, or aphysiologically acceptable salt thereof, is administrated to the bovineup to at least 14 to 56 days prior to slaughter of the bovine. In someembodiments, the period of administration ends upon the bovine'sslaughter. In another embodiment, the bovine is orally administeredlubabegron, or a physiologically acceptable salt thereof, in daily feedrations up to 91 days prior to slaughter.

The term “effective amount”, in the context of administration, refers tothe quantity of lubabegron, or a physiologically acceptable saltthereof, when administered to a bovine, which is sufficient to reduceammonia and/or carbon dioxide emissions from the bovine, as compared toa bovine untreated with lubabegron, or a physiologically acceptable saltthereof. The term “effective amount”, in the context of a feed additive,refers to the quantity of lubabegron, or a physiologically acceptablesalt thereof, included in the animal feed sufficient to reduce ammoniaand/or carbon dioxide emissions from a bovine, as compared to a bovineuntreated with lubabegron, or a physiologically acceptable salt thereof,when the bovine consumes the animal feed.

In some embodiments, lubabegron, or the equivalent of the lubabegronfree base of a physiologically acceptable salt thereof, is administeredin an amount from about 1 mg/day to about 500 mg/day. In someembodiments, lubabegron, or the equivalent of the lubabegron free baseof a physiologically acceptable salt thereof, is administered in anamount from about 5 mg/day to about 500 mg/day. In some embodiments,lubabegron, or the equivalent of the lubabegron free base of aphysiologically acceptable salt thereof, is administered in an amountfrom about 10 mg/day to about 400 mg/day.

In some embodiments, the animal feed contains from about 0.5 to about100 grams of lubabegron, or the equivalent of the lubabegron free baseof a physiologically acceptable salt thereof, per ton of animal feed. Insome embodiments, the animal feed contains from about 0.5 to about 50grams of lubabegron, or the equivalent of the lubabegron free base ofphysiologically acceptable salt thereof, per ton of animal feed. In someembodiments, the animal feed contains from about 1 to about 25 grams oflubabegron, or the equivalent of the lubabegron free base of aphysiologically acceptable salt thereof, per ton of animal feed. In someembodiments, the animal feed contains from about 1.25 to about 20 gramsof lubabegron, or the equivalent of the lubabegron free base of aphysiologically acceptable salt thereof, per ton of animal feed.

In some embodiments, the present disclosure includes the use orinclusion of additional active ingredients. In some embodiments, theadditional active ingredients are one or more selected from the groupconsisting of monensin, tylosin, and melengestrol, or physiologicallyacceptable salts thereof.

The terms and phrases in the Example have their ordinary meaning asunderstood by one of ordinary skill in the art.

EXAMPLE 1 Reduction of Ammonia Emissions

Prepare lubabegron (L) as 4.5 g/lb of Type A Medicated Article. In afacility having at least eight cattle pen enclosures (CPEs), test twocycles of cattle, each cycle representing all dose (0, 1.25, 5, and 20g/ton) and gender (steer and heifer) combinations. For the purpose ofthis example, a cycle refers to a group of 112 animals housedconcurrently. Within each cycle, there are 2 cohorts of animals (56animals per cohort). A cohort refers to a group of same gender animalsrepresenting each of the 4 doses. Up to 4 cycles are used to provide atotal of 4 cohorts per gender.

Upon receipt of the cattle, allocate the cattle to CPEs to acclimate for7 days. After the acclimation phase, for 91 days orally treat via feedone fourth of the cattle allocated to CPEs L 0 g/ton/day; one fourth1.25 g/ton/day; 5 g/ton/day; and 20 g/ton/day (100% dry matter basis).Provide feed and water ad libitum. On day 91, collect body weight andload cattle for transport to the slaughter facility. On day 92,slaughter the cattle and evaluate the carcass. During the study, monitorand collect ammonia gas emissions data. Measure the ammonia emissionsover the treatment period and normalize by body weight (BW) for theperiod (Days 0-7, 0-14, 0-28, 0-56, and 0-91) and hot carcass weight(HCW) (Days 0-91) (g of gas/animal; g of gas/lb of live BW; g of gas/lbof HCW). Using the process described above, the following results areachieved.

Reduction, as compared g of NH₃ gas/lb of live BW g of NH₃ gas/lb of tocontrol (g of NH₃ gas/animal) HCW Day 0-7 0-14 0-28 0-56 0-91 0-91 1.25g/ton  5% 14% 16% 13% 11% 13%  (5%) (12%) (15%) (11%)  (9%)   5 g/ton 8% 17% 21% 18% 14% 16%  (7%) (16%) (20%) (16%) (12%)   20 g/ton 22% 27%26% 19% 15% 17% (21%) (27%) (25%) (19%) (13%)

EXAMPLE 2 Reduction of Carbon Dioxide Emissions

Prepare lubabegron (L) as 4.5 g/lb of Type A Medicated Article. In anappropriate facility having cattle chambers or rooms for individualanimals (chambers), test ten cycles of twelve cattle each, each cyclerepresenting all dose (0, 1.25, 5, and 20 g/ton) with a mixture ofgenders (steer and heifer).

Upon receipt of the cattle, allocate the cattle to chambers to acclimatefor 7 days. After the acclimation phase, for 14 days orally treat viafeed one fourth of the cattle allocated to chambers L 0 g/ton/day; onefourth 1.25 g/ton/day; 5 g/ton/day; and 20 g/ton/day (100% dry matterbasis). Provide feed and water ad libitum. On day 14, collect bodyweight and load cattle for transport to the slaughter facility. On day15, slaughter the cattle and evaluate the carcass. During the study,monitor and collect carbon dioxide gas emissions data. Measure thecarbon dioxide emissions over the treatment period and normalize by bodyweight (BW) for the periods (Days 0-7, 0-14, and 7-14) and hot carcassweight (HCW) (Days 0-14) (g of gas/animal; g of gas/lb of live BW; g ofgas/lb of HCW). Using the process described above, the following resultsare achieved.

Reduction, as compared to control g of CO₂ gas/lb of live BW (g of CO₂gas/animal) g of CO₂ gas/lb of HCW Day 0-7 0-14 7-14 0-14 7-14 1.25g/ton 0% 2% 5% 4%  6% (0.2%)  (3%) (5%) 5 g/ton 3% 6% 9% 7% 10% (4%)(7%) (10%)  20 g/ton 4% 6% 9% 7% 10% (4%) (7%) (9%)

We claim:
 1. A method of reducing ammonia emissions from a bovine inneed thereof comprising orally administering to said bovine lubabegron,or a physiologically acceptable salt thereof.
 2. The method of claim 1,wherein lubabegron, or a physiologically acceptable salt thereof, is thehemifumarate salt thereof.
 3. The method of claim 1, wherein saidlubabegron, or a physiologically acceptable salt thereof, isadministered in an animal feed.
 4. The method of claim 1, wherein one ormore other active ingredients are administered to said bovine, whereinsaid other active ingredients are one or more selected from the groupconsisting of monensin, tylosin, and melengestrol, or physiologicallyacceptable salts thereof.
 5. The method of claim 1, wherein said bovineis a cow.
 6. The method of claim 1, wherein said reduction is per poundof live weight of said bovine.
 7. The method of claim 1, wherein saidreduction is per pound of hot carcass weight of said bovine.
 8. A methodfor reduction of ammonia gas emissions per pound of live weight and hotcarcass weight in beef steers and heifers, the method comprising feedingsaid beef steers and heifers in confinement for slaughter during thelast 14 to 91 days a feed comprising lubabegron or a physiologicallyacceptable salt thereof.
 9. A method of reducing carbon dioxideemissions from a bovine in need thereof comprising orally administeringto said bovine lubabegron, or a physiologically acceptable salt thereof.10. The method of claim 9, wherein lubabegron, or a physiologicallyacceptable salt thereof, is the hemifumarate salt thereof.
 11. Themethod of claim 9, wherein said lubabegron, or a physiologicallyacceptable salt thereof, is administered in an animal feed.
 12. Themethod of claim 9, wherein one or more other active ingredients areadministered to said bovine, wherein said other active ingredients areone or more selected from the group consisting of monensin, tylosin, andmelengestrol, or physiologically acceptable salts thereof.
 13. Themethod of claim 9, wherein said bovine is a cow.
 14. The method of claim9, wherein said reduction is per pound of live weight of said bovine.15. The method of claim 9, wherein said reduction is per pound of hotcarcass weight of said bovine.
 16. The method of claim 1, comprisingadministering an additional ingredient to said bovine, wherein saidadditional ingredient is monensin or a physiologically acceptable saltthereof.
 17. The method of claim 1, comprising administering additionalingredients to said bovine, wherein said additional ingredients aremonensin or a physiologically acceptable salt thereof, and tylosin or aphysiologically acceptable salt thereof.
 18. The method of claim 8,wherein lubabegron, or a physiologically acceptable salt thereof, is thehemifumarate salt thereof.
 19. The method of claim 16, whereinlubabegron, or a physiologically acceptable salt thereof, is thehemifumarate salt thereof.
 20. The method of claim 17, whereinlubabegron, or a physiologically acceptable salt thereof, is thehemifumarate salt thereof.